Studies of families with neurofibromatosis type 1 (NF1) have demonstrated that the severity of this disease depends on modifier genes in the individuals. We are using a mouse model of the malignancies associated with NF1 in which the Nf1 and p53 gene are mutated on the same chromosome and screening for modifier genes in different strains of mice. Importantly, both Nf1 and p53 are mutated in sporadic forms of glioblastoma and sarcoma, thus the understanding of tumor mechanisms gained from this project may have relevance to sporadic nervous system tumors and well as NF1. Using a combination of mouse genetics and expression profiling in tumors, we have identified several regions responsible for resistance to developing malignant peripheral nerve sheath tumors (MPNSTs), and several regions responsible for susceptibility to astrocytoma. The astrocytoma modifier regions affect the location of astrocytoma and the differential susceptibility of males and females. We have identified a candidate modifier gene on mouse chromosome 11 affecting MPNST susceptibility and a candidate modifier gene on mouse chromosome 12 affecting astrocytoma specifically in males. We are working to identify additional candidate modifier genes on other chromosomes, using information gathered from both mouse and humans. These candidate modifiers will then be tested for their role in tumorigenesis in our mouse model and then in human cancers. During fiscal year 2014, we have continued to study the mechanism of how the imprinted gene Grb10 on mouse chromosome 11 acts to block tumor growth of MPNSTs. To identify modifiers of astrocytoma, we are continuing network analysis of genotyping data from 600 backcross mice in collaboration with the CCR Informatics group. We have identified a candidate gene, Cdca7l, for the astrocytoma resistance locus in males (Arlm1) using cross-species comparison with human REMBRANDT and TCGA datasets. Our studies on Cdca7l in cultured cells suggest that this gene acts as an oncogene in male astrocytoma and glioblastoma cells from both mice and humans, but does not show the same action (and may have the opposite effect) in female cells. In fiscal year 2014 we have continued to focus on the mechanism underlying the male-female difference. We have found differential expression of histone demethylases in male and female cells and our preliminary data suggests that these differences interact with Cdca7l levels to regulate gene expression differently in males and females. This research may help to explain why men are at a higher risk for developing astrocytoma and glioblastoma compared to women. We have submitted a manscript on the interaction between Cdca7l and a histone demethylase in fiscal year 2014.